Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

The Critical Role of Passive Permeability in Designing Successful Drugs.

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.

The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro.

Intracellular and Intraorgan Concentrations of Small Molecule Drugs: Theory, Uncertainties in Infectious Diseases and Oncology, and Promise.

The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment. For most highly lipid permeable drugs, this uniform unbound concentration is expected to apply. However, many compounds have restricted lipoidal permeability and are subjected to transport/clearance processes causing a gradient between intracellular and extracellular unbound concentrations even at steady state. Additional concerns arise where the drug target resides in a site of limited vascularity. Many misleading assumptions about drug concentrations and access to drug targets are based on total drug. Correction, if made, is usually by measuring tissue binding, but this is limited by the lack of homogenicity of the organ or compartment. Rather than looking for technology to measure the unbound concentration it may be better to focus on designing high lipoidal permeable molecules with a high chance of achieving a uniform unbound drug concentration. It is hoped this paper will stimulate greater understanding of the path from circulation to cell interior, and thereby in part avoid or minimize the need to provide the experimentally very determining, and sometimes still questionable, answer to this problem.

P-glycoprotein related drug interactions: clinical importance and a consideration of disease states.

IMPORTANCE OF THE FIELD: P-glycoprotein (P-gp) is the most characterized drug transporter in terms of its clinical relevance for pharmacokinetic disposition and interaction with other medicines. Clinically significant P-gp related drug interactions appear restricted to digoxin. P-gp may act as a major barrier to current and effective drug treatment in a number of diseases including cancer, AIDS, Alzheimer's and epilepsy due to its expression in tumors, lymphocytes, cell membranes of brain capillaries and the choroid plexus. AREAS COVERED IN THIS REVIEW: This review summarizes the current understanding of P-gp structure/function, clinical importance of P-gp related drug interactions and the modulatory role this transporter may contribute towards drug efficacy in disease states such as cancer, AIDS, Alzheimer's and epilepsy. WHAT THE READER WILL GAIN: The reader will gain an understanding that the clinical relevance of P-gp in drug interactions is limited. In certain disease states, P-gp in barrier tissues can modulate changes in regional distribution. TAKE HOME MESSAGE: P-gp inhibition in isolation will not result in clinically important alterations in systemic exposure; however, P-gp transport may be of significance in barrier tissues (tumors, lymphocytes, brain) resulting in attenuated efficacy.

Clearing the MIST (metabolites in safety testing) of time: The impact of duration of administration on drug metabolite toxicity.

The importance of mass and concentration, rather than percentage, in determining the safety of risk of metabolites has been the subject of recent scholarship. These studies have not examined the dimension of time as represented by the duration of exposure to the chemical. Reviewing a wide range of clinical information duration of exposure is not a pivotal factor for most types of toxicity, particularly those classified as types A, B or C where concentration and mass are the primary considerations. For instance in idiosyncratic toxicity, classified as type B, where a reactive metabolite is implicated and an immune response is generally required, toxicity can occur early in treatment (1 week to 1 month after starting therapy). In contrast to this type D toxicity in particular carcinogenicity requires that duration of exposure is taken into consideration alongside mass and dose and should be considered the most critical factor. To elicit a response known human carcinogens need a duration of exposure of many years combined with an induction/latency period also measured in years. The perceived risk of a unique human metabolite as a potential health risk by carcinogenesis becomes exceedingly low when the time scale for effect is compared with the age of patients undergoing therapy and their duration of treatment.

Pharmaceutical R&D in the spotlight: why is there still unmet medical need?

Huge amounts of money and knowledge have been poured into biomedical research for decades. Yet, in some disease areas next to no progress has been made in providing medical treatment. Importantly, it is not only neglected diseases where unmet medical need remains, but many diseases of 'rich' countries are also affected. Occasionally, new therapies exacerbate the medical need gap, such as in cancer. Our paper discusses some of the reasons why this might be and why all of society needs to find solutions to address unmet medical need.

Do prodrugs deliver?

This review examines the prodrug concept in the context of conventional prodrugs, which seek to increase systemic concentrations of a drug, and targeted prodrugs, which are designed to increase therapeutic ratio. In general, conventional prodrugs are designed to enhance oral absorption. With both types of prodrug, a pharmacokinetic/pharmacodynamic model must be created to understand the steps required and the barriers that need to be overcome to achieve success. This review highlights the role of polar surface area in identifying drugs that are suitable for oral absorption, and which have the required potency and retention at the intended site of pharmacology.

Metabolites and safety: What are the concerns, and how should we address them?

The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in circulation and excreta, is proposed as the primary source of information on human metabolites from which decisions can be made regarding the need for further risk assessment. Although radiolabel ADME studies yield quantitative metabolite profiles that are commonly reported as a percentage of the total drug related material (for circulating metabolites) and a percentage of total dose (for excretory metabolites), it is essential to convert these values into absolute abundances. The structure of a metabolite, its abundance, the biofluid in which it is observed (circulation or excreta), and the toxicity mechanism of concern serve as the four most important characteristics for determination as to whether further safety consideration is warranted. Metabolites in circulation require consideration for toxicity that can arise by effects on specific receptors and/or enzymes (either target or off-target). Metabolites in excreta require consideration for their potential to indicate a body-burden to chemically reactive intermediary metabolites, which can yield toxicities of nonspecific mechanisms commonly associated with covalent binding (e.g., carcinogenicity, immunoallergic response, etc.). Through an analysis of 24 drugs removed from the market because of human toxicity, it was concluded that further testing of human metabolites would not have yielded any additional information that could have predicted human safety findings because human metabolites would have been present in the animal species routinely used in toxicology testing after the administration of the parent compound.

Is pharmaceutical R&D just a game of chance or can strategy make a difference?

The pharmaceutical industry is currently experiencing turbulent, yet exciting times. Despite widely expressed negative sentiments regarding productivity there are now signs that innovation could yet win the day and bring a fresh wave of breakthrough drugs. Nowhere is this truer than for oncology, which previously was dominated by cytotoxic drugs. Today, however, this field shows exciting progress with the emergence of kinase inhibitors, as well as various antibody-based mechanistic approaches. Similarly, new drug mechanisms have transformed HIV therapy. Are these chance events, or have they come about through strategy? Here, we argue that a complex interplay of chance and strategy is at work in pharmaceutical R&D, separated in time by 10 years or more.